Extended release oral dosage composition

ABSTRACT

A bilayer solid composition comprising (a) an immediate release first layer comprising an anti-allergic effective amount of desloratadine and at least one pharmaceutically acceptable excipient and (b) a sustained release second layer comprising an effective amount of a nasal decongestant, e.g. pseudoephedrine sulfate and a pharmaceutically acceptable sustained release agent wherein the composition contains less than about 2% of desloratadine decomposition products is disclosed. A solid composition comprising an anti-allergic effective amount of desloratadine and at least one, and preferably two pharmaceutically acceptable antioxidants is also disclosed.

BACKGROUND OF THE INVENTION

[0001] This invention relates to oral dosage compositions, including abilayer sustained release oral dosage composition containing a nasaldecongestant, e.g., pseudoephedrine in one layer and the non-sedatingantihistamine, desloratadine in a second layer and having less thanabout 2% of desloratadine degradation products in the compositions. Theoral dosage compositions of this invention are useful for treatingpatients showing the signs and symptoms associated with allergic and/orinflammatory conditions such as the common cold, as well as signs andsymptoms associated with allergic and/or inflammatory conditions of theskin such as dermatitis, and airway passages such as the upperrespiratory disease conditions, perennial allergic rhinitis, seasonalallergic rhinitis and nasal congestion, allergic asthma, and nasalcongestion.

[0002] Desloratadine, also called descarbethoxyloratadine, is disclosedin U.S. Pat. No. 4,659,716 as a non-sedating antihistamine useful as ananti-allergy agent. U.S. Pat. No. 5,595,997 discloses methods andcompositions for treating seasonal allergic rhinitis symptoms usingdesloratadine.

[0003] U.S. Pat. Nos. 4,990,535 and 5,100,675 disclose a twice-a-daysustained release coated tablet wherein the tablet coating comprisesdescarbethoxyloratadine and a hydrophilic polymer and polyethyleneglycol, and the tablet core comprises acetaminophen, pseudoephedrine ora salt thereof, a swellable hydrophilic polymer and pharmaceuticallyacceptable excipients.

[0004] U.S. Pat. No. 5,314,697 discloses an extended release tabletcontaining matrix core comprising pseudoephedrine sulfate and a coatingcomprising loratadine.

[0005] None of the prior art discloses the solid oral dosagecompositions of this invention.

[0006] The successful development of a formulation of adesloratadine-pseudoephedrine twice-a-day and once-a-day products wouldbe desirable, but would require (1) achieving a release rate profile forpseudoephedrine component over an extended period of about twelve hoursor twenty four hours, respectively, while maintaining the safety andeffectiveness of desloratadine, and (2) minimizing impurity formationdue to the interaction between desloratadine and excipients in thepseudoephedrine layer that are incompatible with desloratadine.

[0007] It would be desirable for increased patient compliance to have astable, extended release desloratadine-pseudoephedrine productsubstantially free of desloratadine impurities and additionalpolymorphic forms that is effective and safe when used on a twice-a-dayor once-a-day basis for the treatment, management and/or mitigation ofthe signs and symptoms associated with the common cold, as well asallergic and/or inflammatory conditions of the skin or upper and lowerairway passages such as seasonal and perennial allergic rhinitis andnasal congestion.

SUMMARY OF THE INVENTION

[0008] We have found that desloratadine discolors and decomposes in thepresence of excipients disclosed in the prior art. We have discoveredthat these problems are substantially solved by (a) bilayer solidcompositions of the present invention wherein immediate release layercontains desloratadine combined with a pharmaceutically acceptablecarrier medium comprising a desloratadine protective amount of apharmaceutically acceptable basic salt, and wherein the use of an acidicexcipient in the immediate release layer is substantially avoided or (b)bilayer solid compositions of the present invention wherein adesloratadine-protective amount of at least one pharmaceuticallyacceptable antioxidant is present in at least one layer, and preferably,wherein two of said antioxidants are present in desloratadine-containingimmediate release layer.

[0009] Thus, this invention provides a bilayer solid compositioncomprising (a) an immediate release first layer comprising ananti-allergic effective amount of desloratadine and at least onepharmaceutically acceptable excipient and (b) a sustained release secondlayer comprising an effective amount of a nasal decongestant and apharmaceutically acceptable sustained release agent wherein the totalamount of desloratadine decomposition products in the composition isless than, or equal to, about 2% by weight.

[0010] This invention also provides a bilayer solid compositioncomprising (1) an immediate release first layer comprising ananti-allergic effective amount of desloratadine and adesloratadine-protective amount of a pharmaceutically acceptable waterinsoluble basic calcium, magnesium or aluminum salt, or of adesloratadine-protective amount of at least one pharmaceuticallyacceptable antioxidant; and (2) a sustained release second layercomprising an effective amount of pseudoephedrine or a salt thereof, anda pharmaceutically acceptable sustained release agent, and optionally adesloratadine-protective amount of a pharmaceutically acceptableantioxidant.

[0011] Thus, in one preferred embodiment, this invention provides abilayer solid composition comprising (1) an immediate release firstlayer comprising an anti- allergic effective amount of desloratadine anddesloratadine-protective amount of a pharmaceutically acceptable waterinsoluble basic calcium, magnesium or aluminum salt, and (2) a sustainedrelease second layer comprising an effective amount of pseudoephedrineor a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable sustained release agent. The immediate release layer issubstantially free of, i.e., contains less than about 1%, prefabably,less than about 0.5%, and more prefabably less than about 0.25% ofacidic excipients.

[0012] The total amount of desloratadine decomposition products in thepharmaceutical compositions of this invention is less than, or equal to,about 2.0%, and preferably is less than, or equal to, about 1.4% byweight when such compositions are stored at 25° C. and about 60%relative humidity for extended time periods, e.g., at least about 12 toabout 18 months.

[0013] In another preferred embodiment, this invention provides abilayer solid composition comprising:

[0014] (a) an immediate release first layer comprising: INGREDIENTmg/composition Desloratadine, micronized 2.5 Corn starch 11.0 Dibasiccalcium phosphate dihydrate 53.0 Microcrystalline cellulose 30.22 Talc3.0 FD&C Blue dye No. 2 Aluminium Lake 5627 0.28 TOTAL IN FIRST LAYER100.00

[0015] and

[0016] (b) a second sustained release second layer comprising:INGREDIENT mg/composition Pseudoephedrine Sulfate 120.0 HydroxypropylMethylcellulose 105.0 Microcrystalline cellulose 100.0 Povidone 18.0Silicon Dioxide 5.0 Magnesium stearate 2.0 TOTAL IN SECOND LAYER 350.0

[0017] The total amount of desloratadine decomposition products such asN-formyl-desloratadine (see Chart I) in the above-listed preferredbilayer compositions is less than about 2.0% by weight when suchcompositions are stored at 25° C. and about 60% relative humidity forextended time periods of at least about 15 to about 18 months.

[0018] In another preferred embodiment, the present invention alsoprovides a bilayer solid composition comprising (1) an immediate releasefirst layer comprising an anti-allergic effective amount ofdesloratadine and a desloratadine-protective amount of at least onepharmaceutically acceptable antioxidant; and (2) a sustained releasesecond layer comprising an effective amount of pseudo-ephedrine or apharmaceutically acceptable salt thereof, a pharmaceutically acceptablesustained release agent, and a desloratadine-protective amount of apharmaceutically acceptable antioxidant. The total amount ofdesloratadine decomposition products such as N-formyldesloratadine(seeChart I)in the above-listed preferred bilayer compositions is less thanabout 2.0% by weight when such compositions are stored at 25° C. andabout 60% relative humidity for extended time periods of at least about15 to about 18 months.

[0019] This invention further provides in another preferred embodiment abilayer solid composition comprising (a) an immediate release firstlayer comprising an anti-allergic effective amount of desloratadine andat least one pharmaceutically acceptable excipient and (b) a sustainedrelease second layer comprising an effective amount of pseudoephedrineor a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable sustained release agent and wherein the total amount ofdesloratadine decomposition products in the bilayer solid composition isless than about 2.0% by weight when such compositions are stored at 25°C. and about 60% relative humidity for extended time periods of at leastabout 15 to about 18 months.

[0020] In another preferred embodiment, the present invention alsoprovides a bilayer solid composition comprising (1) an immediate releasefirst layer comprising 5 mg of desloratadine anddesloratadine-protective amount of a pharmaceutically acceptable waterinsoluble basic calcium, magnesium or aluminum salt, and (2) a sustainedrelease second layer comprising 120 mg of pseudoephedrine sulfate, and apharmaceutically acceptable sustained release agent.

[0021] In another preferred embodiment, the present invention alsoprovides a bilayer solid composition comprising (1) a first layercomprising 2.5 mg of desloratadine and a desloratadine-protective amountof at least one pharmaceutically acceptable antioxidant;and (2) a secondlayer comprising 120 mg of pseudoephedrine or a pharmaceuticallyacceptable salt thereof, a pharmaceutically acceptable excipient.Preferably there are two pharmaceutically acceptable antioxidants in thefirst immediate layer.

[0022] In another preferred embodiment, the present invention alsoprovides a bilayer solid composition comprising (1) a first layercomprising 5.0 mg of desloratadine and a desloratadine-protective amountof at least one pharmaceutically acceptable antioxidant;and (2) a secondlayer comprising 120 mg of pseudoephedrine or a pharmaceuticallyacceptable salt thereof, a pharmaceutically acceptable excipient.Preferably there are two pharmaceutically acceptable antioxidants in thefirst immediate layer.

[0023] In another preferred embodiment, the present invention alsoprovides a solid composition comprising 2.5 mg of desloratadine and adesloratadine-protective amount of at least one pharmaceuticallyacceptable antioxidant. Preferably, there are two pharmaceuticallyacceptable antioxidants in the solid compositions.

[0024] In another preferred embodiment, the present invention alsoprovides a solid composition comprising 2.5 mg of desloratadine and adesloratadine-protective amount of at least one pharmaceuticallyacceptable antioxidant. Preferably,there are two pharmaceuticallyacceptable antioxidants in the solid composition.

[0025] We have also found that the total amount of desloratadinedecomposition products in the 2.5 mg and 5.0 mg solid compositions isless than about 2.0%, and at least about 80% of the desloratadine in the2.5 mg and 5.0 mg solid compositions of the present invention dissolvesin 0.1 N HCl at 37° C. in about 45 minutes.

[0026] Thus, the present invention also provides a method of using thesolid compositions of the present invention for treating and/orpreventing allergic and inflammatory conditions of the upper and lowerairway passages and skin which comprises administering to a patient inneed of such treating an effective amount of a solid composition of thepresent invention.

DETAILED DESCRIPTION OF THE INVENTION

[0027] During the course of development of the compositions of thepresent invention, desloratadine was found to be unstable and todiscolor when stored in combination with various excipients such asthose disclosed in U.S. Pat. No. 5,314,697 as part of the matrix corecontaining pseudoephedrine sulfate. We have discovered two solutions tomiminize formation of desloratadine degradation products. In oneembodiment, we incorporate a desloratadine protective amount of apharmaceutically acceptable basic salt in the immediate release layercontaining desloratadine,and substantially avoid the use of an acidicexcipient in the immediate release layer. In the second embodiment, weincorporate a desloratadine-protective amount of at least onepharmaceutically acceptable antioxidant in at least one layer andpreferably we incorporate two of said antioxidants intodesloratadine-containing immediate release layer.

[0028] In the bilayer solid compositions containing a pharmaceuticallyacceptable water insoluble basic calcium, magnesium or aluminum salt, wefound that the excipients in the immediate release layer causingdiscoloration and instability of desloratadine include acidic excipientshaving a pH of less than 7 in water such as organic acids, such asstearic acid, povidone, crospovidone as well as the hydroxycarboxylicacid, ascorbic acid, and carbonyl-containing materials such as lactose,and ethylcellulose and hydroxylpropyl methylcellulose. In this preferredembodiment, we also discovered that it is possible to prepare a bilayertablet containing desloratadine in an immediate release first layer inintimate contact with a sustained release second layer containing anasal decongestant and excipients incompatible with desloratadine byincorporating a desloratadine protective amount of a pharmaceuticallyacceptable water insoluble basic calcium, magnesium or aluminum saltinto the immediate release desloratadine layer, and substantiallyavoiding the use of, that is having less than about 0.1% by weight,prefabably less than about 0.5%, and more prefabably less than about0.25% of acidic excipients in the immediate release layer.

[0029] Binders like povidone and polymers such as hydroxypropylmethylcellulose are useful as a polymer matrix for the sustained releaseof a pharmaceutically acceptable pseudoephedrine salt, preferablypseudoephedrine sulfate, from the sustained release layer.

[0030] We also discovered that metal ions catalyzed were involved in theformation of desloratadine degradation products. In a preferredembodiment, a desloratadine-protective amount of a pharmaceuticallyacceptable anti-oxidant should be present in at least one of thebilayers, preferably one of said antioxidant is present in each layer,and more preferably two pharmaceutically acceptable anti-oxidants arepresent in the desloratadine layer.

[0031] The term “pharmaceutically acceptable antioxidant” as used hereinin reference to desloratadine(“DL”, formula I in the Chart ) means apharmaceutically acceptable chelating agent that protects desloratadinefrom the formation of degradation products including, but not limited tothose of the formulas II-VII listed in the Chart,e.g.,N-formyl-desloratadine or N-formyl DL(formula II in the Chart),N-hydroxylamine of DL (formula V in the Chart ) N-oxide of DL(formula IVin the Chart), and the 3′-hydroxyl N-oxide of DL(formula III in theChart ), N-methyl DL(formula VI in the Chart), and the ketone of formulaVII. The structures listed in the Chart were determined by standardphysiochemical techniques, e.g., LC-MS, and LC-NMR.

[0032] Typically suitable pharmaceutically acceptable antioxidants forDL are pharmaceutically acceptable chelating agents such as thosedisclosed in “Chelating Agents”, pages 764-794, Vol. 5 of KIRTH-OTHMER,ENCYCLOPEDIA OF CHEMICAL TECHNOLOGY, 4 ^(th) Edition, 1993, John Wiley &Sons Inc., N.Y., and preferably including, but not limited to,hydroxycarboxylic acids, such as tartaric acid, citric acid and gluconicacid, and pharmaceutically acceptable salts thereof, aminocarboxylicacids such as iminodiacetic acid, N-methyliminodiacetic acid,nitrolotriacetic acid, edetic acid (ethylenediamine tetraacetic acid),diethylenetriaminepentaacetic acid,1,2-diaminocyclohexanetetraaceticacid or N-hydroxylethylenediaminetriacetic acid, and pharmaceuticallyacceptable salts thereof such as the alkali and alkaline earthsalts,e.g., edetate calcium disodium, edetate disodium, edetatetrisodium, and edetate tetrasodium. Edetate disodium and citric acid arethe preferred pharmaceutically acceptable antioxidants. Use of thehydroxycarboxylic acid, ascorbic acid, is to be avoided

[0033] The desloratadine protective amount of a pharmaceuticallyacceptable antioxidant in the desloratadine immediate release layer isin the range of about 0.1% to about 10% by weight, preferably about 1%to 8% or about 1% to about 6%, more preferably about 3% to about 8%, orabout 4% to about 6%, or most preferably about 5%. In a preferredembodiment of this invention, two antioxidants are present in theimmediate release desloratadine layer, one antioxidant, e.g., edeatedisodium, in an amount of about 1% to about 8%, preferably about 3% toabout 8%, more preferably about 4% to about 6%, or most preferably about5%, and the second antioxidant, e.g., citric acid, is present in anamount of about 1% to about 8%, preferably about 3% to about 8%, morepreferably about 4% to about 6%, or most preferably about 5%. Thepharmaceutically acceptable antioxidant in the pseudoephedrine sulfate(“PES”) sustained release layer is in the range of 0% to about 10%,preferably about 0.1% to about 10%, or about 0.1% to about 3%, morepreferably about 1 to about 2%, and most more preferably about 1.0%. Ina preferred embodiment of the present invention, about 1.0% by weight ofa pharmaceutically acceptable antioxidant, e.g., edetate disodium, ispresent in the PES sustained release layer. In another preferredembodiment, about 6% by weight of a mixture of two pharmaceuticallyacceptable antioxidants, e.g., edetate disodium and citric acid, arepresent in the DL immediate release layer in a ratio of about 5:1 toabout 1:5, preferably about 5:1, and about 1% of a pharmaceuticallyacceptable antioxidant, e.g., edetate disodium, is present in thesustained release layer. In another preferred embodiment, about 5% byweight of one pharmaceutically acceptable antioxidant, e.g., edetatedisodium, is present in the desloratadine immediate release layer.

[0034] In other preferred embodiments, about 5.0 mg of desloratadine ispresent in the immediate release layer, and 120 mg of the nasaldecongestant, pseudoephedrine sulfate, is present in the sustainedrelease layer (see Examples 4,5 & 6). In one preferred embodiment, thedibasic phosphate salt preferably dibasic calcium phosphate dihydrate ispresent in the desloratadine immediate release layer and nopharmaceutically acceptable antioxidant is present in either layer (seeExample 4). In another preferred embodiment, 5.0 mg of desloratadine andabout 0.1 to about 10% of at least one antioxidant is present in thedesloratadine immediate release layer, preferably about 4% to about 6%of a mixture of two antioxidants, e.g., edetate disodium and citricacid, in a ratio of 5:1 to 1:1, preferably in a ratio of 5:1, and about0.1% to about 10% preferably about 0.1% to about 5%, more preferablyabout 0.1% to about 3%, most more preferably about 1.0% of anantioxidant, e.g., edetate disodium, is present in the PES sustainedrelease layer (see Examples 5&6).

[0035] The desloratadine was found to have an acceptable immediaterelease profile from the immediate release layer (80% release in 0.1 NHCl in less than about 45 min.) and contain less than about 2% ofdesloratadine degradation products even after storage for at least 18months at 25° C. and about 60% relative humidity (“RH”).

[0036] In another preferred embodiment, the present invention alsoprovides a solid composition comprising 2.5 mg of desloratadine and adesloratadine-protective amount of at least one pharmaceuticallyacceptable antioxidant. Preferably, there are two pharmaceuticallyacceptable antioxidants in the solid compositions. See Example 9. Inanother preferred embodiment, the present invention also provides asolid composition comprising 5.0 mg of desloratadine and adesloratadine-protective amount of at least one pharmaceuticallyacceptable antioxidant. Preferably, there are two pharmaceuticallyacceptable antioxidants in the solid composition. See for example,Example 10. The desloratadine protective amount of a pharmaceuticallyacceptable antioxidant in the 5.0 mg and 2.5 mg solid compositions is inthe range of about 0.1% to about 10% by weight, preferably about 1% to8% or about 1% to about 6%, more preferably about 3% to about 8%, orabout 4% to about 6%, or most preferably about 5%. In a preferredembodiment of this invention, two antioxidants are present in the 5.0 mgand 2.5 mg solid compositions; one antioxidant, e.g., edeate disodium,in an amount of about 1% to about 8%, preferably about 3% to about 8%,more preferably about 4% to about 6%, or most preferably about 5%, andthe second antioxidant, e.g., citric acid, is present in an amount ofabout 1% to about 8%, preferably about 3% to about 8%, more preferablyabout 4% to about 6%, or most preferably about 5%. In another preferredembodiment, about 6% by weight of a mixture of two pharmaceuticallyacceptable antioxidants, e.g., edetate disodium and citric acid, arepresent in the 5.0 mg and 2.5 mg solid compositions in a ratio of about5:1 to about 1:5, preferably about 1:1,. It has been surprisingly foundthat stearic acid could be used in place of talc to overcome a toolingproblem in the 5.0 mg and 2.5 mg solid compositions containing twopharmaceutically acceptable antioxidants, e.g., edetate disodium andcitric acid, without adversely affecting the total amount ofdesloratadine decomposition products.

[0037] We have found that the total amount of desloratadinedecomposition products in the 5.0 mg and 2.5 mg solid compositionscontaining two pharmaceutically acceptable antioxidants, e.g., edetatedisodium and citric acid,is less than about 2.0%, and preferably about1.5% by weight or less after storage at 25 c and 60% RH for extendedtime periods of at least 12 up to 15 months. In addition, at least about80% of the desloratadine in the 5.0 mg and 2.5 mg solid compositionscontaining two pharmaceutically acceptable antioxidants, e.g., edetatedisodium and citric acid, dissolves in 0.1 N HCl at 37° C. in about 45minutes.

[0038] In another preferred embodiment, a desloratadine-protectiveamount of a pharmaceutically acceptable anti-oxidant should be presentin at least one of the bilayers, preferably one of said antioxidant ineach layer.

[0039] The two layers of the bilayer tablets of this invention may be inintimate contact with one another, or have a layer at the interfaces ofthe two layers. The layer at the interfaces of the two layers may be awater-swellable film-forming polymer containing one or morepharmaceutically acceptable excipients or the layer may also contain atleast one pharmaceutically acceptable antioxidant.

[0040] The term “in intimate contact” as used herein in reference to thetwo layers forming the bilayer tablet means that there is with no filminterface between the two layers.

[0041] The term “water-swellable film-forming neutral or cationiccopolymeric ester,” as used herein means neutral and cationic copolymersof ethyl acrylate and substituted unsubstituted methyl or ethylmethacrylate esters.

[0042] Typically suitable water swellable film-forming neutralcopolymeric esters include neutral copolymers of ethyl acrylate andmethyl metharylate such as are available from Pharma Poloymers, acompany of the Hüls Group under the EUDRAGIT® Tradename; EUDRAGIT NE30D.and Kollicoat available from BASF, Mt Olive, N.J. An aqueous dispersioncontaining 30% by weight of a neutral copolymer based on ethyl crylateand methyl methoacrylate (average molecular weight of approximately800,000) is preferred.

[0043] Typically suitable water-swellable film-forming cationicco-polymeric esters include cationic co-polymerers based ondimethylaminoethylmethacrylate and a neutral methacrylic ester such asthe EUDRAGIT E copolymers available from Pharma Polymers as a 12.5%solution (EUDRAGIT E 12.5) or as solid (EUDRAGIT E 100) and quaternayammonium copolymers described in USP/NF as “Amononio methacrylatecopolymer, Type A” and Type “B”. Such copolymers are available asaqueous dispersions of copolymers of acrylic and methacrylic acid esterswith a low (substitution) content of quaternary ammonium groups presentas salts, (e.g., quaternary ammonium chlorides). Type A and Type B areavailable as 30% aqueous dispersions under the EUDRAGIT RL 30D andEUDRAGIT RS 30D tradenames, respectively. Use of the water-swellablefilm-from neutral co-polymeric esters based on ethyl acrylate andmethacrylate is preferred.

[0044] The term “water soluble film modifier” as used herein means afilm-forming agent which modifies the water-swellable characteristics ofthe film-forming neutral or cationic copolymeric esters useful in thelayer at the interface of the bilayer compositions of the presentinvention. A typically suitable water soluble film-modifying agent is alow viscosity (≦20 cps) cellulose such as low viscosity hydroxypropylmethyl cellulose, low viscosity hydroxylethyl methyl cellulose; lowviscosity sodium carboxymethyl cellulose or a polyethylene glycolselected from polyethylene glycol 200 to polyethylene glycol 8000.

[0045] Use of a polyethylene glycol 6000 to polyethylene glycol 8000 asa film modifier is preferred.

[0046] The phrase “allergic and inflammatory conditions of the skin andairway passages” means those allergic and inflammatory conditions andsymptoms found on the skin and in the upper and lower airway passagesfrom the nose to the lungs. Typical allergic and inflammatory conditionsof the skin and upper and lower airway passages include seasonal andperennial allergic rhinitis, non-allergic rhinitis, asthma includingallergic and non-allergic asthma, sinusitis, colds (in combination witha NSAID, e.g., aspirin ibuprofen or APAP) and/or a decongestant e.g.pseudoephedrine), dermatitis, especially allergic and atopic dermatitis,and urticaria and symptomatic dermographism as well as retinophathy, andsmall verssel diseases, associated with diabetes mellitus.

[0047] The amount of desloratadine effective for treating or preventingallergic and inflammatory conditions of the skin and upper and lowerairway passages will vary with the age, sex, body weight and severity ofthe allergic and inflammatory condition of the patient. Typically, theamount of desloratadine effective for treating or preventing suchallergic and inflammatory conditions is in the range of about 2.5 mg/dayto about 60 mg/day, preferably about 2.5 mg/day to about 20 mg/day, orabout 4.0 mg/day to about 15 mg/day, or about 5.0 mg/day to about 10mg/day, more preferably about 5.0 mg/day to about 10.0 mg/day, and mostpreferably about 5.0 mg/day in one dose or in two divided doses of 2.5mg/dose.

[0048] Desloratadine is a non-sedating long acting histamine antagonistwith potent selective peripheral H1-receptor antagonist activity.Following oral administration, loratadine is rapidly metabolized todescarboethoxyloratadie or desloratadine, a pharmacologically activemetabolite. In vitro and in vivo animal pharmacology studies have beenconducted to assess various pharmacodynamic effects of desloratadine andloratadine. In assessing antihistamine activity in mice (comparison ofED₅₀ value), desloratadine was relatively free of producing alterationsin behavior alterations in behavior, neurologic or autonomic function.The potential for desloratadine or loratadine to occupy brainHI-receptors was assessed in guinea pigs following i.p. administrationand results suggest poor access to central histamine receptors fordesloratadine or loratadine.

[0049] In addition to antihistaminic activity, desloratadine hasdemonstrated anti-allergic and anti-inflammatory activity from numerousin vitro and in vivo tests. These in vitro tests (mainly conducted oncells of human origin) have shown that desloratadine can inhibit manyevents in the cascade of allergic inflammation.

[0050] These anti-inflammatory effects for desloratadine are independentof the H1-antagonist effect of desloratadine and include:

[0051] The release of inflammatory mediators histamine, truptase,leukotriene and prostaglandin D2 from mast cells;

[0052] The release of inflammatory cytokines including IL-4, IL-6, IL-8and IL-13;

[0053] The release of the inflammatory chemokines such as RANTES(regulated upon activation, normal T cell expressed and presumablysecreted);

[0054] Superoxide anion production of polymorphonuclear neutrophils;

[0055] The expression of cell adhesion molecules such as intracellularadhesion molecules (ICAM-1) and P-selection in endothelial cells; and

[0056] Eosinophil migration and adhesion

[0057] In vivo studies also suggest that an inhibitory effect ofdesloratadine on allergic bronchospasm and cough can also be expected.

[0058] The clinical efficacy and safety of desloratadine has beendocumented in over 3,200 seasonal allergic rhinitis patients in 4double-blind, randomized clinical trials. The results of these chemicalstudies demonstrated the efficacy of desloratadine in the treatment ofadult and adolescent patients with seasonal rhinitis.

[0059] The nasal decongestants useful in the present invention includephenylpropanolamine, phenylephrine and and pseudoephedrine.Pseudoephedrine as well as pharmaceutically acceptable acid additionalsalts, e.g., those of HCl or H₂SO₄, is a sympathomimetic drug recognizedby those skilled in the art as a safe therapeutic agent effective fortreating nasal congestion and is commonly administered orally andconcomitantly with an antihistamine for treatment of nasal congestionassociated with allergic rhinitis. The use of pseudoephedrine as a nasaldecongestant in the present invention is preferred; the use of about 120mg pseudoephedrine sulfate in the extended release layer is morepreferred. However, lesser amounts of pseudoephedrine sulfate may beused in combination with desloratadine, e.g., in combination with the2.5 and 5.0 solid compositions of the present invention such asdescribed in Examples 9 and 10.

[0060] In the course of development of the compressed bilayer oraldosage composition of this invention, it was discovered that theselection of the polymers for the extended release layer was critical toachieve the desired extended release period of at least 12 hours,forpseudoephedrine sulfate. For example, the use of hydroxypropylmethylcellulose 4,000 cps or 15,000 cps as polymers in the matrix coredid not provide this more preferred extended release period of at least16 hours for dose of pseudoephedrine sulfate. We discovered that only byselecting for inclusion into the matrix core of specific weight ratiosof three specific polymers was the desired pseudoephedrine releaseprofile achieved. Only by combining (1) about one part by weight,preferably 1.05 parts by weight of hydroxypropyl methylcellulose 2208USP, 100,000 cps with (2) about one part by weight, preferably 1.0 partsby weight of microcrystalline cyellulose together with (3) about0.15-0.20 part by weight., preferably 0.17-0.18 parts by weight ofpovidone (per 1.05 parts by weight of hydroxypropyl methylcellulose) asa secondary binder was the more preferred extended release profile of atleast 12 hours for pseudoephedrine sulfate from the extended releaselayer. The extended release layer also contains specific amounts ofsilicon dioxide as a glidant and magnesium stearate as a lubricant. Thetablet hardness 20±4 Strong-Cobb Units (SCU) is not greatly affected bythe higher level of lubricant (6mg/tablet) but it is preferred tomaintain the lubricant level at 1/9 part by weight of lubricant to onepart by weight of povidone as secondary binder.

[0061] The term “lubricant” as used herein refers to a substance addedto the dosage form to enable the dosage form, e.g., a tablet, after ithas been compressed to release from the mold or die.

[0062] Suitable lubricants include talc, magnesium stearate, calciumstearate, stearic acid, hydrogenated vegetable oils and the like.Preferably, magnesium stearate or talc is used.

[0063] The term “glidants” as used herein refers to a substance, such asan anti-caking agent, which improves the flow characteristics of apowder mixture.

[0064] Suitable glidants include silicon dioxide and talc. Preferably,silicon dioxide is used.

[0065] The term “binders” as used herein means any material that isadded to pharmaceutical compositions to help hold such compositionstogether and release the medicament therefrom.

[0066] Suitable binders are selected those found in NF XVIII, page 2206(1995) and include povidones, starches, celluloses, alginates, and gumsand low molecular weight hydroxypropyl melthyl celluloses, especiallyhydroypropyl methyl celluose 2910.

[0067] The term “pharmaceutically acceptable water insoluble basiccalcium, magnesium and aluminium salts” as used herein means thepharmaceutically acceptable carbonates, phosphates, silicates andsulfates of calcium, magnesium and aluminum or mixtures thereof.Typically suitable pharmaceutically acceptable basic salts includecalcium sulfate anhydrous, hydrates of calcium sulfate, such as calciumsulfate dihydrate, magnesium sulfate anhydrous, hydrates of magnesiumsulfate, dibasic calcium phosphate, dibasic calcium silicate, magnesiumtrisilicate, magnesium phosphate, aluminum silicate, and hydrates ofmagnesium phosphate, aluminum phosphate; and calcium phosphate is morepreferred. The use of dibasic calcium phosphate dihydrate is mostpreferred.

[0068] The desloratadine-protective amount of a pharmaceuticallyacceptable water insoluble basic calcium, magnesium or aluminum salt isin the range of about 50-60% of the DL immediate release layer, and thew/w ratio of the pharmaceutically acceptable water insoluble basiccalcium, magnesium or aluminum salt to DL is in the range of about 8:1to about 40:1, more preferably is in the range of about 10:1 to about20:1, and most preferably is in the range of about 10:1 to about 11:1.

[0069] In the preferred embodiment of the present invention wherein adesloratadine protective amount of a pharmaceutically acceptableantioxidant is present, the water insoluble basic calcium salt is notpresent in the immediate release layer containing desloratadine; in itsplace, at least one, preferably two pharmaceutically acceptableantioxidants are present, e.g., edetate sodium and citric acid and theamount of microcrystalline cellulose is increased. In addition, when thepharmaceutically acceptable antioxidant is used in place of the waterinsoluble basic calcium, magnesium or aluminum salt, the povidone in thesustained release layer is replaced by another binder, preferably a lowmolecular weight hydroxypropyl methyl cellulose (“HPMC”), preferablyHPMC 2910.

[0070] In the preparation of the bilayer tablet, the sustained releaselayer is compacted first. The immediate release second layer is added ontop and a compression force sufficient to form a bilayer tablet isapplied in the range of 8-12 kilo Newtons, preferably about 9 kiloNewtons(kN).

[0071] The dried sustained release granulation is milled and blendedwith requisite amounts of silicon dioxide and magnesium stearate. In apreferred embodiment, a pharmaceutically acceptable blue dye containingEDTA as a chelating agent is incorporated into the immediate releasedesloratadine layer. Use of a pharmaceutically acceptable blue dye, e.g.FD& C blue dye No. 2 Aluminum Lake 5627 is preferred.

EXAMPLE 1

[0072] This example illustrates preparation of the preferred oral dosagecomposition of this invention. The ingredients and specific amountsthereof are listed below.

[0073] A. Method of Manufacture of the Immediate Release Layer

[0074] 1. Prepare starch paste by dispersing the paste portion of cornstarch into purified water in a suitable container equipped with anagitator.

[0075] 2. While mixing, heat the contents to approximately 95° C. andmaintain the temperature for approximately 30 minutes.

[0076] 3. After Step 2 is completed, add an additional purified waterand allow the starch paste to cool to approximately 50° C.

[0077] 4. While mixing, add desloratadine to the starch paste. Continuemixing during the granulation step.

[0078] 5. Pass the FD&C blue No. 2 aluminum lake containing EDTA as achelating, e.g., Spectra Spray Med Blue, with the required amount ofdibasic calcium phosphate through a suitable sieve or mill.

[0079] 6. Charge to a suitable fluid bed processing bowl the remainingdibasic calcium phosphate dihydrate, the milled material from Step 5, aportion of the corn starch, and a portion of microcrystalline cellulose.Place the processing bowl into the fluid bed processor.

[0080] 7. Fluidize the powder bed until the product temperature reachesapproximately 29° C.

[0081] 8. Begin granulating the powder by pumping the starch paste fromStep 4 into the fluidized bed at a suitable spray rate and a bedtemperature of approximately 22° C.

[0082] 9. Continue to dry the granulation at an inlet air temperature ofapproximately 60° C. until a final loss on drying (LOD) of 2% or less isachieved.

[0083] 10. Pass the dried granulation through a suitable sieve or mill.

[0084] 11. Charge the granulation to a suitable blender and add therequisite amounts of the remaining portion of microcrystallinecellulose, corn starch, and talc. Blend for 5 minutes.

[0085] B. Manufacture of Sustained Release Mix

[0086] 1. Charge purified water and alcohol to a suitable containerequipped with an agitator.

[0087] 2. Dissolve povidone in the water/alcohol mixture. Continuemixing for a minimum of 10 minutes.

[0088] 3. Mix hydroxypropyl methylcellulose, pseudoephedrine sulfate andmicrocrystalline cellulose in a suitable granulator.

[0089] 4. Granulate the mix with the povidone solution, using additionalwater/alcohol mixture if necessary to achieve the appropriategranulation consistency.

[0090] 5. Dry the wet granulation at approximately 50° C. in a suitabledryer until the loss on drying (LOD) is between 1% and 3%.

[0091] 6. Pass the dried granulation through a suitable sieve or mill.

[0092] 7. Charge the milled granulation to a suitable blender.

[0093] 8. Pass the silicon dioxide through a No. 30 mesh screen into theblender.

[0094] 9. Blend the requisite amount of screened silicon dioxide withthe granulation for approximately 10 minutes in a suitable blender.

[0095] 10. Pass the magnesium stearate through a No. 30 mesh screen.

[0096] 11. Blend the requisite amount of screened magnesium stearatewith the mix from Step 9 for 5 minutes.

[0097] C. Compression

[0098] Compress the two blends to specifications as bilayer tabletsusing a suitable double-layer tablet press using a compression force of9 k Newtons. Compress the sustained release layer first. Tablet Weight:450 mg±5%

[0099] Sustained release layer: 350 mg±5%

[0100] Immediate release layer: 100 mg±5%

[0101] Hardness: 20±4 SCU (Strong Cobb units)

[0102] The following bilayer tablet was prepared using the aboveprocedure. INGREDIENT mg/composition Desloratadine Immediate ReleaseLayer: Desloratadine, micronized  2.5 Corn Starch NF/Ph. Eur.  11.0Dibasic Calcium Phosphate Dihydrate USP/Ph. Eur.  53.0 MicrocrystallineCellulose NF/Ph. Eur./JP  30.22 Talc USP/Ph. Eur.  3.0 Dye FD&C Blue No.2 Aluminium Lake 5627  0.28 Water Purified USP/Ph. Eur. — TOTAL 100.00and Pseudoephedrine Sulfate Sustained Release Layer PseudoephedrineSulfate USP 120.0 Hydroxypropyl Methylcellulose 2208, USP, 105.0 100,000cps (K100 M)/Ph. Eur. Microcrystalline Cellulose NF/Ph. Eur./JP 100.0Povidone USP/Ph. Eur./JP  18.0 Silicon Dioxide NF  5.0 MagnesiumStearate NF/Ph. Eur. JP(Non-Bovine)  2.0 Water Purified USP/Ph. Eur. —Alcohol USP/3A Alcohol — TOTAL 350.0 TOTAL TABLET 450.0

EXAMPLE 2

[0103] The procedure of Example 1 was used; edetate disodium was used inplace of the dibasic calcium salt and the amount of microcrystallinecellulose in the DL layer was increased. Edetate disodium was used inthe sustained release layer and hydroxypropyl methylcellulose 2910 wasused in place of povidone. INGREDIENT mg/composition DesloratadineImmediate Release Layer: Desloratadine, micronized  2.5 Corn StarchNF/Ph. Eur.  8.0 Microcrystalline Cellulose NF/Ph. Eur./JP  71.35Edetate Disodium  5.0 Talc USP/Ph. Eur.  3.0 Dye FD&C Blue No. 2Aluminium Lake 5627  0.15 Water Purified USP/Ph. Eur. — TOTAL 100.00 andPseudoephedrine Sulfate Sustained Release Layer Pseudoephedrine SulfateUSP 120.0 Hydroxypropyl Methylcellulose 2208, USP/Ph. Eur. 105.0Microcrystalline Cellulose NF/Ph. Eur./JP 103.5 Edetate Disodium  3.5Hydroxypropyl Methylcellulose 2910 USP/Ph. Eur./JP  10.5 Silicon DioxideNF  5.0 Magnesium Stearate NF/Ph. Eur. JP(Non-Bovine)  2.5 WaterPurified USP/Ph. Eur. — Alcohol USP/3A Alcohol — TOTAL 350.0 TOTALTABLET 450.0

EXAMPLE 3

[0104] The procedure of Example 2 was used, but 1 mg of citric acid wasadded to the DL layer and the amount of microcrystalline cellulose wasdecreased by 1 mg. INGREDIENT mg/composition Desloratadine ImmediateRelease Layer: Desloratadine, micronized  2.5 Corn Starch NF/Ph. Eur. 18.0 Edetate Disodium  5.0 Citric Acid  1.0 Microcrystalline CelluloseNF/Ph. Eur./JP  70.35 Talc USP/Ph. Eur.  3.0 Dye FD&C Blue No. 2Aluminium Lake 5627  0.15 Water Purified USP/Ph. Eur. — TOTAL 100.00 AndPseudoephedrine Sulfate Sustained Release Layer Pseudoephedrine SulfateUSP 120.0 Hydroxypropyl Methylcellulose 2208, 100,000 cps 105.0 (K100M)USP/Ph. Eur. Microcrystalline Cellulose NF/Ph. Eur./JP 103.5 EdetateDisodium  3.5 Hydroxypropyl Methylcellulose 2910  10.5 Silicon DioxideNF  5.0 Magnesium Stearate NF/Ph. Eur. JP(Non-Bovine)  2.5 WaterPurified USP/Ph. Eur. — Alcohol USP/3A Alcohol — TOTAL 350.0 TOTALTABLET 450.0

EXAMPLE 4

[0105] The procedure of Example 1 was used. The bilayer tablet ofExample 1 was modified by including 5.0 mg of desloratadine in theimmediate release layer-(a 24 hour dose)-with the appropriate changes inamounts of the other ingredients and using the 12-hr dosepseudoephedrine sustained release layer of Example 1. Hardness:20±4 SCU(Strong Cobb units) INGREDIENT mg/composition Desloratadine ImmediateRelease Layer: Desloratadine, micronized  5.0 Corn Starch NF/Ph. Eur. 11.0 Dibasic Calcium Phosphate Dihydrate USP/Ph. Eur.  53.0Microcrystalline Cellulose NF/Ph. Eur./JP  27.72 Talc USP/Ph. Eur.  3.0Dye FD&C Blue No. 2 Aluminium Lake 5627  0.28 Water Purified USP/Ph.Eur. — TOTAL 100.00 and Pseudoephedrine Sulfate Sustained Release LayerPseudoephedrine Sulfate USP 120.0 Hydroxypropyl Methylcellulose 2208,1000,00 cps 105.0 (K100 M)USP/Ph. Eur. Microcrystalline Cellulose NF/Ph.Eur./JP 100.0 Povidone USP/Ph. Eur./JP  18.0 Silicon Dioxide NF  5.0Magnesium Stearate NF/Ph. Eur. JP(Non-Bovine)  2.0 Water PurifiedUSP/Ph. Eur. — Alcohol USP/3A Alcohol — TOTAL 350.0 TOTAL TABLET 450.0

EXAMPLE 5

[0106] The procedure of Example 1 was used and the bilayer tablet ofExample 4 was modified by replacing the dibasic calcium phosphatedihydrate in the immediate release layer with 10 mg of edetate disodiumand increasing the amount of microcrystalline cellulose by 2.7 mg.Hardness:20±4 SCU (Strong Cobb units) INGREDIENT mg/compositionDesloratadine Immediate Release Layer: Desloratadine, micronized  5.0Corn Starch NF/Ph. Eur.  36.0 Microcrystalline Cellulose NF/Ph. Eur./JP142.7 Edetate Disodium  10.0 Talc USP/Ph. Eur.  6.0 Dye FD&C Blue No. 2Aluminium Lake 5627  0.30 Water Purified USP/Ph. Eur. — TOTAL 200.00 andPseudoephedrine Sulfate Sustained Release Layer Pseudoephedrine SulfateUSP 120.0 Hydroxypropyl Methylcellulose 2208, 1000,00 cps 105.0 USP/Ph.Eur. Microcrystalline Cellulose NF/Ph. Eur./JP 103.5 HydroxypropylMethylcellulose 2910  10.5 Edetate Disodium  3.5 Silicon Dioxide NF  5.0Magnesium Stearate NF/Ph. Eur. JP(Non-Bovine)  2.5 Water PurifiedUSP/Ph. Eur. — Alcohol USP/3A Alcohol — TOTAL 350.0 TOTAL Tablet Weight550.0

EXAMPLE 6

[0107] The bilayer tablet of Example 5 was modified by adding 2.0 mg ofcitric acid to the immediate release layer and decreasing the amount ofmicrocrystalline cellulose by 2.7 mg and using the pseudoephedrinesustained release layer of Example 1. Hardness:20±4 SCU (Strong Cobbunits) INGREDIENT mg/composition Desloratadine Immediate Release Layer:Desloratadine, micronized  5.0 Corn Starch NF/Ph. Eur.  36.0Microcrystalline Cellulose NF/Ph. Eur./JP 140.7 Edetate Disodium  10.0Citric Acid  2.0 Talc USP/Ph. Eur.  6.0 Dye FD&C Blue No. 2 AluminiumLake 5627  0.30 Water Purified USP/Ph. Eur. — TOTAL 200.00 AndPseudoephedrine Sulfate Sustained Release Layer Pseudoephedrine SulfateUSP 120.0 Hydroxypropyl Methylcellulose 2208, 1000,00 cps 105.0 USP/Ph.Eur. Microcrystalline Cellulose NF/Ph. Eur./JP 103.5 HydroxypropylMethylcellulose 2910  10.5 Edetate Disodium  3.5 Silicon Dioxide NF  5.0Magnesium Stearate NF/Ph. Eur. JP(Non-Bovine)  2.5 Water PurifiedUSP/Ph. Eur. — Alcohol USP/3A Alcohol — TOTAL 350.0 TOTAL Tablet Weight550.0

EXAMPLE 7

[0108] The bilayer tablet of Example 5 was modified by replacing thetalc with an equivalent weight of stearic acid, and by adding anadditional 8.0 mg of citric acid to the immediate release layer anddecreasing the amount of microcrystalline cellulose by 8.0 mg andreplacing 4.0 g of the microcrystalline cellulose and all of thehydroxypropyl methylcellulose and edetate disodium with 18.0 g ofpopovidone the pseudoephedrine in the sustained release layer of Example6. INGREDIENT mg/composition Desloratadine Immediate Release Layer:Desloratadine, micronized  5.0 Corn Starch NF/Ph. Eur.  36.0Microcrystalline Cellulose NF/Ph. Eur./JP 132.7 Edetate Disodium USP 10.0 Citric Acid Anhydrous, USP  10.0 Stearic Acid, NF.  6.0 Dye FD&CBlue No. 2 Aluminium Lake 5627  0.30 Water Purified USP/Ph. Eur. — TOTAL200.00 And Pseudoephedrine Sulfate Sustained Release LayerPseudoephedrine Sulfate USP 120.0 Hydroxypropyl Methylcellulose 2208,1000,00 cps 105.0 USP/Ph. Eur(K100 M). Microcrystalline Cellulose NF/Ph.Eur./JP  99.5 Povidone, USP  18.0 Silicon Dioxide NF  5.0 MagnesiumStearate NF/Ph. Eur. JP(Non-Bovine)  2.5 Water Purified USP/Ph. Eur. —Alcohol USP/3A Alcohol — TOTAL 350.0 TOTAL Tablet Weight 550.0

EXAMPLE 8

[0109] The bilayer tablet of Example 7 was modified by decreasing theweight of all ingredients in the desloratadine immediate release layerby 50% and using the sustained release layer of Example 7 INGREDIENTmg/composition Desloratadine Immediate Release Layer: Desloratadine,micronized  2.5 Corn Starch NF/Ph. Eur.  18.0 Microcrystalline CelluloseNF/Ph. Eur./JP  66.35 Edetate Disodium USP  5.0 Citric Acid Anhydrous,USP  5.0 Stearic Acid, NF.  3.0 Dye FD&C Blue No. 2 Aluminium Lake 5627 0.15 Water Purified USP/Ph. Eur. — TOTAL 100.00 And PseudoephedrineSulfate Sustained Release Layer Pseudoephedrine Sulfate USP 120.0Hydroxypropyl Methylcellulose 2208, 1000,00 cps 105.0 USP/Ph. Eur(K100M). Microcrystalline Cellulose NF/Ph. Eur./JP  99.5 Povidone, USP  18.0Silicon Dioxide NF  5.0 Magnesium Stearate NF/Ph. Eur. JP(Non-Bovine) 2.5 Water Purified USP/Ph. Eur. — Alcohol USP/3A Alcohol — TOTAL 350.0TOTAL Tablet Weight 450.0

EXAMPLE 9

[0110] A desloratadine(2.5 mg) tablet was prepared by using thedesloratadine immediate release layer of Example 8. INGREDIENTmg/composition Desloratadine, micronized  2.5 Corn Starch NF/Ph. Eur. 18.0 Microcrystalline Cellulose NF/Ph. Eur./JP  66.35 Edetate DisodiumUSP  5.0 Citric Acid Anhydrous, USP  5.0 Stearic Acid, NF.  3.0 Dye FD&CBlue No. 2 Aluminium Lake 5627  0.15 Water Purified USP/Ph. Eur. — TOTALTablet Weight 100.00

EXAMPLE 10

[0111] A desloratadine(5.0 mg) tablet was prepared by using thedesloratadine immediate release layer of Example 7. INGREDIENTmg/composition Desloratadine, micronized  5.0 Corn Starch NF/Ph. Eur. 36.0 Microcrystalline Cellulose NF/Ph. Eur./JP 132.7 Edetate DisodiumUSP  10.0 Citric Acid Anhydrous, USP  10.0 Stearic Acid, NF.  6.0 DyeFD&C Blue No. 2 Aluminium Lake 5627  0.30 Water Purified USP/Ph. Eur. —TOTAL TABLET WEIGHT 200.00

[0112] The in vitro dissolution profile of the tablets of Examples 1-10were measured in a stirred 0.1 N HCl solution at 37° C. (1st hour) andthereafter in a stirred phosphate buffer having a pH of 7.5 at 37° C.The 80% of desloratadine in the immediate release layers was dissolvedwithin the first 30 minutes and the total dose of pseudoephedrinesulfate in the sustained release layers of Examples 1-8 was slowlyreleased via erosion and dissolution mechanisms over a period of atleast 12 hours.(with 30-45% in 1 hr, 50-605% in 2 hrs. and ≧80% in 6hrs).

[0113] Similar results would be expected if a decongestant effectiveamount of another pharmaceutically acceptable pseudoephedrine salt,e.g., pseudoephedrine hydrochloride was used in place of pseudoephedrinesulfate.

[0114] The compositions of the present invention are useful fortreatment of allergic and/or inflammatory conditions of the skin (e.g.urticaria) and the upper and lower airway passages including the nasaland non-nasal symptoms of perennial and seasonal allergic rhinitisincluding nasal congestion in a patient in need of such treating. Theprecise dosage and dosage regimen may be varied by the attendingclinician in view of the teachings herein depending upon therequirements of the patient, e.g., the patient's age, sex and theseverity of the allergic and/or inflammatory condition being treated.Determination of the proper dosage and dosage regimen for a particularpatient will be within the skill of the attending clinician. While wehave hereinabove presented a number of preferred embodiments of thisinvention by way of example, it is apparent that the scope of theinvention is to be defined by the scope of the appended claims.

What is claimed is:
 1. A bilayer solid composition comprising (1) afirst layer comprising an anti-allergic effective amount ofdesloratadine and a desloratadine-protective amount of apharmaceutically acceptable water insoluble basic calcium, magnesium oraluminum salt, or of a desloratadine-protective amount of at least onepharmaceutically acceptable antioxidant; and (2) a second layercomprising an effective amount of pseudoephedrine or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient,and optionally, a desloratadine-protective amount of at least onepharmaceutically acceptable antioxidant.
 2. The bilayer solidcomposition of claim 1 wherein the first layer is in intimate contactwith the second layer
 3. The bilayer solid composition of claim 1wherein at least about 80% of the desloratadine dissolves in a 0.1 N HClsolution at 37° C. in about 45 minutes.
 4. The bilayer solid compositionof claim 1 wherein total amount of desloratadinedegradation products isless than or equal to about 2.0% by weight.
 5. The bilayer solidcomposition of claim 1 wherein about 0.1% to about 10% of at least onepharmaceutically acceptable antioxidant is present in the first layer.6. The bilayer solid composition of claim 1 wherein adesloratadine-protective amount of at least one pharmaceuticallyacceptable antioxidant is present in the second layer.
 7. The bilayersolid composition of claim 1 wherein a pharmaceutically acceptableaterinsoluble basic calcium, magnesium or aluminum salt antioxidant ispresent in the first layer.
 8. The bilayer solid composition of claim 1wherein the anti-allergic effective amount of desloratadine in the firstlayer is about 2.5 mg.
 9. The bilayer solid composition of claim 1wherein the anti-allergic effective amount of desloratadine in the firstlayer is about 5.0 mg.
 10. The bilayer solid composition of claim 1wherein two pharmaceutically acceptable antioxidants are present in thefirst layer.
 11. A bilayer solid composition comprising (1) a firstlayer comprising an anti-allergic effective amount of desloratadine anddesloratadine-protective amount of a pharmaceutically acceptable waterinsoluble basic calcium, magnesium or aluminum salt, and (2) a secondlayer comprising an effective amount of pseudoephedrine or apharmaceutically acceptable salt thereof.
 12. The bilayer solidcomposition of claim 11 wherein the first layer is in intimate contactwith the second layer
 13. The bilayer solid composition of claim 11wherein at least about 80% of the desloratadine dissolves in a 0.1 N HClsolution at 37° C. in about 45 minutes.
 14. The bilayer solidcomposition of claim 11 wherein total amount of desloratadinedegradation products is less than or equal to about 2.0% by weight. 15.The bilayer solid composition of claim 11 wherein the anti-allergiceffective amount of desloratadine in the first layer is about 2.5 mg.16. The bilayer solid composition of claim 11 wherein the anti-allergiceffective amount of desloratadine in the first layer is about 5.0 mg.17. A bilayer solid composition comprising (1) a first layer comprisingan anti-allergic effective amount of desloratadine and adesloratadine-protective amount of at least one pharmaceuticallyacceptable antioxidant; and (2) a second layer comprising an effectiveamount of pseudoephedrine or a pharmaceutically acceptable salt thereof,a pharmaceutically acceptable excipient, and a desloratadine-protectiveamount of at least one pharmaceutically acceptable antioxidant, andwherein total amount of desloratadine degradation products is less thanor equal to about 2.0% by weight.
 18. The bilayer solid composition ofclaim 17 wherein the first layer is in intimate contact with the secondlayer
 19. The bilayer solid composition of claim 17 wherein at leastabout 80% of the desloratadine dissolves in a 0.1 N HCl solution at 37°C. in about 45 minutes.
 20. The bilayer solid composition of claim 17wherein about 0.1% to about 10% of at least one pharmaceuticallyacceptable antioxidant is present in the first layer.
 21. The bilayersolid composition of claim 17 wherein the anti-allergic effective amountof desloratadine in the first layer is about 2.5 mg.
 22. The bilayersolid composition of claim 17 wherein the anti-allergic effective amountof desloratadine in the first layer is about 5.0 mg.
 23. The bilayersolid composition of claim 17 wherein two pharmaceutically acceptableantioxidants are present in the first layer.
 24. A bilayer solidcomposition comprising (a) an immediate release first layer comprisingan anti-allergic effective amount of desloratadine and at least onepharmaceutically acceptable excipient and (b) a sustained release secondlayer comprising an effective amount of a pseudoephedrine, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient, and wherein total amount of desloratadinedegradation products is less than or equal to about 2% by weight, andwherein at least about 80% of the desloratadine dissolves in a 0.1N HClsolution at 37° C. in about 45 minutes.
 25. The bilayer solidcomposition of claim 24 wherein total amount of desloratadinedegradation products is less than or equal to about 1.5% by weight. 26.A bilayer solid composition comprising a first layer and a second layer,wherein the first layer is an immediate release layer comprising:INGREDIENT mg/composition Desloratadine, micronized  2.5 Corn Starch 11.0 Dibasic Calcium Phosphate Dihydrate  53.0 MicrocrystallineCellulose  30.22 Talc  3.0 Dye FD + C Blue No. 2 Aluminium Lake  0.28TOTAL 100.00

and and wherein the second layer is an sustained release layercomprising INGREDIENT mg/composition Pseudoephedrine Sulfate 120.0Hydroxypropyl Methylcellulose 105.0 Microcrystalline cellulose 100.0Povidone  18.0 Silicon Dioxide  5.0 Magnesium stearate  2.0 TOTAL 350.0

and wherein total amount of desloratadine degradation products is lessthan or equal to about 2% by weight.
 27. The bilayer solid compositionof claim 26 wherein at least about 80% of the desloratadine dissolves ina 0.1N HCl solution at 37° C. in about 45 minutes.
 28. A bilayer solidcomposition comprising (1) a first layer comprising 2.5 mg ofdesloratadine and desloratadine-protective amount of a pharmaceuticallyacceptable water insoluble basic calcium, magnesium or aluminum salt,and (2) a second layer comprising 120 mg of pseudoephedrine or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient, and wherein total amount of desloratadinedegradation products is less than or equal to about 2% by weight
 29. Thebilayer solid composition of claim 28 wherein at least about 80% of thedesloratadine dissolves in a 0.1N HCl solution at 37° C. in about 45minutes.
 30. A bilayer solid composition comprising (1) a first layercomprising 5 mg of desloratadine and desloratadine-protective amount ofat least one pharmaceutically acceptable antioxidant, and (2) a secondlayer comprising 120 mg of pseudoephedrine or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient,and wherein total amount of desloratadine degradation products is lessthan or equal to about 2% by weight.
 31. The bilayer solid compositionof claim 30 wherein at least about 80% of the desloratadine dissolves ina 0.1N HCl solution at 37° C. in about 45 minutes
 32. A bilayer solidcomposition comprising a first layer and a second layer, wherein thefirst layer is an immediate release layer comprising: INGREDIENTmg/composition Desloratadine, micronized  5.0 Corn Starch NF/Ph. Eur. 11.0 Dibasic Calcium Phosphate Dihydrate USP/Ph. Eur.  53.0Microcrystalline Cellulose NF/Ph. Eur./JP  27.72 Talc USP/Ph. Eur.  3.0Dye FD&C Blue No. 2 Aluminium Lake 5627  0.28 TOTAL 100.00

and wherein the second layer is a sustained release layer comprising:INGREDIENT mg/composition Pseudoephedrine Sulfate USP 120.0Hydroxypropyl Methylcellulose 2208, 1000,00 cps 105.0 USP/Ph. Eur.Microcrystalline Cellulose NF/Ph. Eur./JP 100.0 Povidone USP/Ph. Eur./JP 18.0 Silicon Dioxide NF  5.0 Magnesium Stearate NF/Ph. Eur.JP(Non-Bovine)  2.0 TOTAL 350.0 TOTAL TABLET 450.0

and wherein total amount of desloratadine degradation products in thecomposition is less than or equal to about 2% by weight.
 33. The bilayersolid composition of claim 32 wherein at least about 80% of thedesloratadine dissolves in a 0.1N HCl solution at 37° C. in about 45minutes.
 34. A bilayer solid composition comprising a first layer and asecond layer, wherein the first layer is an immediate release layercomprising: INGREDIENT mg/composition Desloratadine, micronized  5.0Corn Starch NF/Ph. Eur.  36.0 Microcrystalline Cellulose NF/Ph. Eur./JP132.7 Edetate Disodium USP  10.0 Citric Acid Anhydrous, USP  10.0Stearic Acid, NF.  6.0 Dye FD&C Blue No. 2 Aluminium Lake 5627  0.30Water Purified USP/Ph. Eur. — TOTAL 200.00 :

and wherein the second layer is a sustained release layer comprisingINGREDIENT mg/composition Pseudoephedrine Sulfate USP 120.0Hydroxypropyl Methylcellulose 2208, 1000,00 cps 105.0 USP/Ph. Eur(K100M). Microcrystalline Cellulose NF/Ph. Eur./JP  99.5 Povidone, USP  18.0Silicon Dioxide NF  5.0 Magnesium Stearate NF/Ph. Eur. JP(Non-Bovine) 2.5 Water Purified USP/Ph. Eur. — Alcohol USP/3A Alcohol — TOTAL 350.0TOTAL Tablet Weight 550.0;

and wherein total amount of desloratadine degradation products in thecomposition is less than or equal to about 2% by weight.
 35. The bilayersolid composition of claim 33 wherein at least about 80% of thedesloratadine dissolves in a 0.1N HCl solution at 37° C. in about 45minutes.
 36. A bilayer solid composition comprising a first and secondlayer, wherein the first layer is an immediate release first layercomprises: INGREDIENT mg/composition Desloratadine, micronized  2.5 CornStarch NF/Ph. Eur.  18.0 Microcrystalline Cellulose NF/Ph. Eur./JP 66.35 Edetate Disodium  5.0 Citric Acid  5.0 Stearic Acid USP/Ph. Eur. 3.0 Dye FD&C Blue No. 2 Aluminium Lake 5627  0.15 TOTAL 100.00

and wherein the second layer is a sustained release layer comprising:INGREDIENT mg/composition Pseudoephedrine Sulfate USP 120.0Hydroxypropyl Methylcellulose (K100 M) 105.0 2208, 1000,00 cps USP/Ph.Eur. Microcrystalline Cellulose NF/Ph. Eur./JP  99.5 Povidone USP K-30 18.0 Silicon Dioxide NF  5.0 Magnesium Stearate NF/Ph. Eur.JP(Non-Bovine)  2.5 TOTAL 350 TOTAL Tablet Weight 450.0

and wherein total amount of desloratadine degradation products is lessthan or equal to about 2% by weight.
 37. The bilayer solid compositionof claim 36 wherein at least about 80% of the desloratadine dissolves ina 0.1N HCl solution at 37° C. in about 45 minutes.
 38. A method oftreating allergic and inflammatory conditions of the upper and lowerairway passages and skin which comprises administering to a patient inneed of such treating an effective amount of the bilayer solidcomposition of claim
 1. 39. A method of treating nasal congestionassociated with allergic and inflammatory conditions of the upper andlower airway passages and skin which comprises administering to apatient in need of such treating an effective amount of the bilayersolid composition of claim
 1. 40. A method of treating urticaria whichcomprises administering to a patient in need of such treating aneffective amount of the bilayer solid composition of claim
 1. 41. Amethod of treating the nasal and non-nasal symptoms of perennial andseasonal allergic rhinitis which comprises administering to a patient inneed of such treating an effective amount of the bilayer solidcomposition of claim 1.